Protein kinases are a class of phosphotransferases that transfer γ-phosphate group of ATP to specific amino acid residues of a substrate to phosphorylate proteins, so as to exert their physiological and biochemical functions. The protein kinases are an important class of kinases. They play a major role in signal transduction in two aspects: one aspect is to regulate activity of proteins through phosphorylation; the other is to amplify the signal cascade through phosphorylation of proteins, so as to initiate a cellular response.
Abnormal protein kinase activity is not only closely related to abnormity in a certain link of a series of signal transduction pathways inside and outside cells, such as proliferation, apoptosis, and metastasis of tumors, etc., but also is a major reason for a series of other human diseases involving inflammation or proliferative response, such as rheumatoid arthritis, cardiovascular diseases and diseases of nervous system, asthma, psoriasis and the like. More than 400 human diseases are known to be directly or indirectly related to protein kinases, which makes protein kinases become another pivotal class of medicine targets following G-protein coupled receptors.
The protein kinase family consists of more than 500 members and is generally classified into two types, protein tyrosine kinases (PTKs) and serine-threonine kinases. According to the position of the kinase in the cell, the protein kinase family also can be classified into receptor kinases and non-receptor kinases (also known as intracellular kinases). The receptor kinases are generally tyrosine kinases, also referred to as receptor tyrosine kinases (RTKs). The receptor kinases are composed of extracellular, transmembrane, and intracytoplasmic portions, and a catalytically active portion of the kinases is located in the intracytoplasmic portion. Most serine-threonine kinases are located in cells and belong to the non-receptor kinases or cytosolic kinases.
Typical representatives of the RTK family are growth factor receptors, which has at least 19 subfamilies. Several major subfamilies are described as follow:
(a) HER family tyrosine receptor kinases, including epithelial growth factor receptor (EGFR), HER2, HER3 and HER4. The EGFR is a target of several synthesized small molecule medicines, such as Tarceva®, Tykerb® and monoclonal antibody Erbitux®, for the treatment of non-small cell lung cancer.
(b) A family consisting of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R), and insulin receptor-related receptor (IRR), in which the IGF-1R is a recognized anti-cancer target. However, the IGF-1R is too similar to IR, and especially the intracellular kinase portion of the IGF-1R has an amino acid sequence that is 100% identical to that of IR, so that an inhibition of IGF-1R activity is usually accompanied with an inhibition of IR activity. There is evidence proving that IR is also an effective anti-cancer target. However, it is necessary to find a balance between benefits and safety risks when using IR inhibitors for anticancer due to their risk of elevating blood glucose.
(c) A family of platelet-derived growth factor receptors (PDGFRs), including PDGFR-α, PDGFR-β, CSF1R, c-KIT, and c-fms. c-KIT is also a molecular target of a leukemia therapeutic medicine Gleevec® for the treatment of gastrointestinal stromal tumors.
(d) A family of vascular endothelial growth factor receptors (VEGFRs), including Fms-like tyrosine kinase 1 (FLT1) (or VEGFR1), KDR (or VEGFR-2), and FLT4 (or VEGFR3). The members of this subfamily are molecular targets of Sutent® and Naxavar®.
(e) A family of fibroblast growth factor receptors (FGFRs), including FGFR1, FGFR2, FGFR3 and FGFR4 and seven ligands FGF1, FGF2, FGF3, FGF4, FGF5, FGF6 and FGF7. The members of this subfamily are molecular targets of medicines that are still in clinical trials.
(f) MET family, including c-Met, also known as human hepatocyte growth factor receptor or hHGFR, and RON. c-Met plays a pivotal role in the growth and metastasis of initial tumors. The medicines targeting on c-Met are still in clinical trials.
(g) RET family, RET is a receptor for members of GDNF family, including RET51, RET43 and RET9 isoforms. The medicines targeting on RET are still in clinical trials.
(h) Eph family, which is the largest family of tyrosine receptor kinases, consisting of 16 receptors (EPHA1, EPHA2, EPHA3, EPHA4, EPHA5, EPHA6, EPHA7, EPHA8, EPHA9, EPHA10, EPHB1, EPHB2, EPHB3, EPHB4, EPHB5, EPHB6) and 9 ligands (EFNA1, EFNA2, EFNA3, EFNA4, EFNA5, EFNB1, EFNB2, EFNB3). These members play an important role in the growth of animals, and some members play a role in the development of tumor.
AXL, also known as UFO/ARK/Tyro, is another important tyrosine receptor kinase, whose ligand is the vitamin K-dependent growth promoting factor GAS6. The first discovery of AXL was as a transforming gene for chronic myeloid leukemia (CML). An overexpression of AXL can be found in metastatic colon cancer, thyroid cancer, breast cancer, prostate cancer, and melanoma. Inhibition of AXL activity can inhibit the growth, spreading and metastasis of tumor.
Non-receptor kinases do not have the extracellular portion and the transmembrane portion, i.e., the entire kinase is located in the cytoplasm. At least 24 non-receptor kinases are now known and can be divided into 11 subfamilies: Src, Frk, Btk, CsK, Abl, Zap70, Fes, Fps, Fak, Jak and AcK subfamilies. The Src subfamily is the largest, including Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, AUR1, AUR2, and Yrk kinases. For more detailed information, see Neet, K.; Hunter, T. Genes to Cells 1996, 1, 147-169 and the literature cited therein. Although there are several non-receptor kinases of tyrosine kinase, most non-receptor kinases belong to the serine-threonine kinases. Several members are molecular targets for the leukemia therapeutic medicines such as Gleevec® and Sprycel®.
As described above, receptor kinases and non-receptor kinases serving as anti-tumor targets have been well demonstrated in clinical and practical applications and multiple anti-tumor medicines have been approved for market and the treatment of patients. In addition to tumor therapy, inhibition of abnormality of receptor kinases and non-receptor kinases can also be used to treat diseases including, but not limited to, psoriasis, cirrhosis, diabetes, diseases involving angiogenesis, diseases involving restenosis, eye diseases, age-related macular degeneration, rheumatoid arthritis and other inflammations, immune system diseases such as autoimmune diseases, cardiovascular diseases such as atherosclerosis, kidney diseases, and the like. Therefore, it is essential to continue to develop inhibitors of these kinases.